CORRESPONDENCE

Facult6 Xavier Bichat Universit& Paris VII Paris, France

CALCIUM ANTAGONISTS AND AMINOGLYCOSIDE NEPHROTOXICITY To the Editor: Russell and Churchill (Am J Med 1989; 87: 306-315) report on calcium antagonists and ischemic acute renal failure (ARF). We would like to emphasize that calcium antagonists could also be beneficial in the prevention of aminoglycoside-induced ARF. In our laboratory, we have studied the prevention of netilmicin nephrotoxicity by diltiazem in men and in an animal model. Diltiazem (60 mg three times a day for 7 days) in human volunteers could prevent the increase in urinary N-acetylglutamate and the loss of dilution ability induced by netilmicin (4.5 mglkg every day for 7 days) [l]. In a rabbit model of moderate ARF (glomerular filtration rate [GFR] lowered by 50%) induced by netilmicin, we have shown that animals receiving diltiazem in a therapeutic dosage (1 mg/kg three times a day), concurrent with netilmicin (20 mg/kg three times a day) for 5 days, had a GFR similar to that in controls. Diltiazem was protective without altering arterial blood pressure, renal plasma flow, and cortical accumulation or tubular uptake of netilmicin. Netilmicin pharmacokinetics (maximum concentration, area under the curve, distribution volume) were unchanged by diltiazem. Diltiazem might prevent netilmicin toxicity through mechanisms involving glomerular mesangium rather than a selective reduction in afferent and preglomerular resistance [2]. In summary, calcium antagonists appear to prevent aminoglycoside-induced ARF, probably by pathways different from those involved in the prevention of ischemic ARF. Calcium antagonists could be useful in patients undergoing renal transplantation, cardiopulmonary bypass, or resection of aortic aneurysm in whom gram-negative infections, potentially requiring aminoglycoside therapy, are frequently associated with hemodynamically mediated transient reduction in GFR. 0. LORTHOLARY, V. MAHE, F. BLANCHET. C. CARBON,

M.D. M.D. Ph.D. M.D.

INSERM

1. Mahe V, Blanchet F. Sera N. et a/: Drlbazem, a calcrum entry blocker, protects human volunteers agarnst netrlmrcrn nephrotoxrcity (abstr 295). 28th InterscIence Conference on Antimrcrobral Agents and Chemotherapy. Los Angeles, California, 1988. 2. Lortholary 0. Blanchet F, Seta N, Amrrault P. Carbon C. Tubular oarameters bv diltrazem at theraoeuttc dosage agarnst chronic nettlmrctn renal toxicity In rabbits (abstr 294). 29th Interscience Conference on AntImIcrobial Agents and Chemotherapy. Houston, Texas, 1989. Submitted October

10, 1989, and accepted November 14. 1989

PROSPECTIVE TESTING OF FALL RISK INDEX To the Editor: The fall risk index presented by Tinetti et al (Am J Med 1986; 80: 429-434) was prospectively evaluated under the direction of Dr. Charles Beauchamp at the Sioux Falls Veterans Administration Medical Center to test this clinical prediction rule on new patients in a different clinical setting [l]. The incidence and consequences of falls among the elderly continue to be a major concern for all health-care providers, as evidenced by the large number of related articles in medical, nursing, and quality-assurance journals. Accurately predicting patients’ risk of falling from systematic clinical observations should help physicians and other providers identify which patients require interventions to reduce their potential for falls [1,2]. Direct observation by a multidisciplinary team of a sample of 26 male patients was used to collect baseline data as identified in the Tinetti study. Patients were then assigned to one of three risk groups: yes, predicted to fall; 30% chance of falling; not predicted to fall. Reports of falls were reviewed during the following 4 months and data were analyzed by frequency tables and discriminant analysis. Actual occurrences were demonstrated to be consistent with predicted occurrences in the frequency tabulation, and 23 of 26 participants were classified correctly by discriminant analysis. One value of this index is in predicting or identifying patients very likely or unlikely to fall (12 patients in this study). However, the April

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majority of patients (14) were grouped in the middle area, in which falls could not be predicted. Another, perhaps more significant, value of the index is in providing reproducible, quantified data sets with which to report falls and intrinsic factors among groups of patients. Although the number of articles related to falls in the elderly continues to grow, there is no standardized method for reporting on patient variables and the effects of various interventions, making comparisons an “apples and oranges” approach. The Tinetti index could fill this void. MARCELLINE

HARRIS,

R.N.,

M.S.

College of Nursing South Dakota State University Brookings, South Dakota 1. Wasson JH, Sox H, Neff R, Goldman L, Clinrcal predtctton rules: applications and methodological standards N Engl J Med 1985. 313: 793-799. 2. Pinhold E. Kroenke K, Hanley J. Kussman M. Twyman P. Carpenter J: Funcbonal assessment of the elderly. a comparison of standard Instruments with clintcal judgment. Arch Intern Med 1987; 147: 48448a. Submitted October 25, 1989, and accepted November 14. 1989

DIAGNOSIS AND TREATMENT OF HIGH-GRADE MYELOMA To the Editor: I read with great interest the recent clinicopathologic conference in which the differential diagnosis of multiple myeloma with transformation versus immunoblastic lymphoma was raised in a patient who developed high-grade malignancy 1.5 years after detection of a monoclonal gammopathy (Am J Med 1989; 87: 577-582). We have recently described “high-grade myeloma” defined by high serum levels of lactic dehydrogenase (LDH) with high-grade lymphoma features including extraosseous disease, renal failure, high µglobulin levels, hypercalcemia, and, most important, a rapidly fatal disease course [l]. Although this syndrome is more prevalent among patients with refractory multiple myeloma, elevated serum LDH levels were also found to confer a poor prognosis among newly diagnosed patients receiving VAD (vincristine-AdriamycinTM-dexamethasone) chemotherapy. We recommended that LDH analysis should become part of the standard myJournal

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eloma work-up, and we have recently developed a flow cytometric assay of cytoplasmic LDH content to identify small tumor cell populations displaying such high-grade features already at diagnosis. Although I agree with the author’s opinion that such high-grade myelomas are similar to immunoblastic lymphomas, cytoplasmic immunoglobulin analysis should be helpful in resolving this issue. I believe that high-grade myeloma is quite similar to the blastic phase of chronic myelogenous leukemia, resembling either acute lymphoblastic leukemia or acute myeloblastic leukemia, in which cytogenetic characteristics of the original disease process are yet retained. Thus, routine application of cytoplasmic immunoglobulin analysis with demonstration of monoclonal light chain expression should be useful in distinguishing “transformed” myeloma from primary immunoblastic lymphoma. In regard to treatment for highgrade myeloma, we have recently reported on the activity of the EDAP regimen (etoposide, dexamethasone, cytosine arabinoside, and cis-platinum), which induces objective responses in 40% of patients with VAD- and even highdose melphalan-refractory myeloma, regardless of LDH levels [2]. More recent experience with this lymphoma-like intensive treatment regimen suggests that frequent and durable remissions in high-grade myeloma are obtainable. BARTBARLOGIE,M.D. University

of Arkansas Little

for Medical Sciences Rock, Arkansas

1. Barlogie B, Smallwood L. Smith T, Alexanian R: Hugh serum levels of lactic dehydrogenase identify a hrgh-grade lymphoma-like myeloma. Ann Intern Med 1989; 110: 521-525. 2. Barlogie B. Velasquez W. Alexanian R, Cabanrllas F: Etoposrde. dexamethasone, cytarabrne. and crsplatin In vincrrstlne, doxorubicrn. and dexamethasone-refractorymyeloma. J Clin Oncol 1989; 7: 1514-1517. Submrtted

November

29, 1989, and accepted December 6, 1989

POSSIBLE CONTRAINDICATION OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN PATIENTS WITH HEREDITARY ANGIOEDEMA To the Editor: Angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril, and lisinopril) are being in446

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creasingly prescribed for hypertension and chronic congestive heart failure. I would like to point out a possible contraindication to their use. Patients with hereditary angioedema (HAE) have a deficiency of Cl esterase inhibitor, which may result in enhanced formation of bradykinin [l-3]. It has been suggested that bradykinin (which induces vascular permeability without pruritus) might be responsible for angioedema in these patients [l-4]. ACE is identical to kininase; consequently, ACE inhibitors may block bradykinin metabolism. Therefore, patients with HAE who are receiving an ACE inhibitor may theoretically be at risk of more severe episodes of angioedema. Increased sensitivity to bradykinin might also be responsible for the angioedema that occurs in 0.1% to 0.2% of patients after initiation of treatment with an ACE inhibitor bl. GILLIANM. SHEPHERD,M.D. The New York Hoswital-Cornell Mldical Center New York, New York 1. Schaprra M. Srlver LD, Scott CF. eta/:Prekallikrein activation and high-molecular-werght krnrnogen consumption In hereditary angloedema. N Engl J Med 1983; 308: 1050-1053. 2. Talamo RC. Haber E, Austen KF: A radiormmunoassay for bradykinrn rn plasma and synovral flurd. J Lab Clin Med 1969: 74: 816-827. 3. Curd JG, Programs U Jr, Cochrane CG: Detection of active kallikrern In induced blister fluids of hereditary angloedema patients. J Exp Med 1980; 152: 742747. 4. Fields TH, Ghehrehiwet B, Kaplan AP: Krnrn formation In heredrtary angloedema: evrdence against kinin derivatron from C2 and in support of “spontaneous” formation of bradykrnin. J Allergy Clin lmmunol 1983; 72: 54-60. 5. Slater EE, Merril DD, Guess HA, etal:Clinrcal profrle of angloedema assocrated with angrotensrn converting-enzyme Inhibitron. JAMA 1988; 260: 967-970. Submitted November

3. 1989. and accepted December 6, 1989

SULFONYLUREA FAILURE IN NON-INSULIN-DEPENDENT DIABETES MELLITUS To the Editor: I read with interest the report of Groop et al (Am J Med 1989; 87: 183-190) in which it was suggested that secondary failure to treatment with sulfonylureas is determined by the disease itself rather than by patient-related factors, and that noted in the nonresponders a high rate of basal hepatic glucose output, which was less suppressed by euglycemic hyperinsulinemia, impaired peripheral glucose metabo-

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lism, and insulin deficiency. This explained the cause of the failure of oral antidiabetic therapy in only 56% of those studied. However, the fact that 47% of the nonresponders and only 16% of the responders were receiving antihypertensive therapy with diuretics, selected p-blockers, and prazosin was mentioned only in the description of the characteristics of the subjects and was ignored in the interpretation of the data. It is more common for a hypertensive patient to develop diabetes than for a patient with diabetes to develop hypertension [l]. Women [2] and men [3] taking diuretics with or without P-blockers have an increased risk of developing diabetes. This is most likely due to the effects of antihypertensive therapy in combination with the insulin resistance associated with essential hypertension [4]. Dornhorst et al [5] have shown that in persons with non-insulin-dependent diabetes mellitus, a mild increase in the fasting blood glucose and hemoglobin Ai levels will occur with propranolol, a modest increase in these parameters will occur with hydrochlorothiazide, and severe decompensation in glycemic control will occur when hydrochlorothiazide and propranolol are used in combination. Selective Pi-adrenergic blockers (atenolol and metoprolol) also cause worsening of the glycemic status [6]. Thiazide-induced glucose intolerance may be modulated through hypokalemiainduced reduction of insulin release, effects on the enterohepatic axis, increased insulin resistance due to impaired glucose utilization with the blockade of metabolic phosphorylation, and altered hepatic glucose metabolism [7]. pBlockers cause hyperglycemia by inhibition of insulin release, increased hepatic glycogenolysis, decreased peripheral glucose sensitivity and utilization, and perhaps by an elevation of growth hormone [7]. Prazosin, on the other hand, has been reported to increase insulin sensitivity in obese patients with hypertension [8]. Thus, with the variable of antihypertensive therapy not included in the statistical analysis in this study, the results lose their significance. I would be interested in knowing if the same results would be found if only those subjects not receiving antihypertensive therapy were included in the study, or if the